title: Valrubicin activates PKCa in keratinocytes: a conceivable mode of action in treating hyper-proliferative skin diseases.
abstract: BACKGROUND
  Valrubicin is a semisynthetic anthracycline developed as an anti-cancer drug able to ameliorate psoriasis and non-melanoma skin cancer (NMSC) by topical application in animal models. Valrubicin decreases cell proliferation, and induces apoptosis; however its mode of action is still unknown. Valrubicin localizes in the cytoplasm and its valerate moiety resembles diacylglycerol, an activator of protein kinase C (PKC) α, which belongs to the PKC family of cytoplasmic serine/threonine protein kinases. PKCα is observed in the suprabasal layers of normal skin and is associated to keratinocyte growth arrest and differentiation processes. In hyper-proliferative skin diseases the presence of PKCα is altered.
  
  
  OBJECTIVE
  The aim of the present study was to investigate valrubicin's mode of action in keratinocytes by studying its possible effect on PKCα activation.
  
  
  METHODS
  PKCα's characteristic to translocate from the cytoplasm to the cellular membrane when activated was assessed by measuring the amount of PKCα in the soluble and membrane-bound protein fractions isolated from valrubicin stimulated keratinocytes and by visualizing PKCα in stimulated cells over time. Downstream signaling was investigated by measuring the amount of phosphorylated Myristoylated Alanine-rich C-kinase substrate (MARCKS) and extracellular signal-regulated kinases (ERK) 1/2 of valrubicin-stimulated keratinocytes. To investigate whether there was a direct interaction between valrubicin and PKCα, an activity assay employing purified PKCα protein was used.
  
  
  RESULTS
  Valrubicin activates PKCα in vitro as shown by PKCα's translocation and phosphorylation of downstream signaling molecules.
  
  
  CONCLUSIONS
  Valrubicin stimulates PKCα activity and downstream signaling which may contribute to its beneficial effect in psoriasis and NMSC.
authors.forename: Ina Groenkjaer
authors.initials: IG
authors.lastname: Laugesen
authors.forename: Eva
authors.initials: E
authors.lastname: Hauge
authors.forename: Stine Maria
authors.initials: SM
authors.lastname: Andersen
authors.forename: Karin
authors.initials: K
authors.lastname: Stenderup
authors.forename: Elisabeth
authors.initials: E
authors.lastname: de Darkó
authors.forename: Tomas Norman
authors.initials: TN
authors.lastname: Dam
authors.forename: Cecilia
authors.initials: C
authors.lastname: Rosada
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects / Q000201:enzymology*; D050356:Lipid Metabolism / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D010766:Phosphorylation; D051571:Protein Kinase C-alpha / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D012871:Skin Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D047908:Intracellular Signaling Peptides and Proteins; C000619710:MARCKS protein, human; D008565:Membrane Proteins; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; C016163:valrubicin; D004317:Doxorubicin; D051571:Protein Kinase C-alpha